Immune related and inflammatory diseases are the manifestation or consequence of fairly complex, often multiple interconnected biological pathways which in normal physiology are critical to respond to insult or injury, initiate repair from insult or injury, and mount innate and acquired defense against foreign organisms. Disease or pathology occurs when these normal physiological pathways cause additional insult or injury either as directly related to the intensity of the response, as a consequence of abnormal regulation or excessive stimulation, as a reaction to self, or as a combination of these.
Though the genesis of these diseases often involves multistep pathways and often multiple different biological systems/pathways, intervention at critical points in one or more of these pathways can have an ameliorative or therapeutic effect. Therapeutic intervention can occur by either antagonism of a detrimental process/pathway or stimulation of a beneficial process/pathway.
Many immune related diseases are known and have been extensively studied. Such diseases include immune-mediated inflammatory diseases, non-immune-mediated inflammatory diseases, infectious diseases, immunodeficiency diseases, neoplasia, etc.
T lymphocytes (T cells) are an important component of a mammalian immune response. T cells recognize antigens which are associated with a self-molecule encoded by genes within the major histocompatibility complex (MHC). The antigen may be displayed together with MHC molecules on the surface of antigen presenting cells, virus infected cells, cancer cells, grafts, etc. The T cell system eliminates these altered cells which pose a health threat to the host mammal. T cells include helper T cells and cytotoxic T cells. Helper T cells proliferate extensively following recognition of an antigen -MHC complex on an antigen presenting cell. Helper T cells also secrete a variety of cytokines, i.e., lymphokines, which play a central role in the activation of B cells, cytotoxic T cells and a variety of other cells which participate in the immune response.
A central event in both humoral and cell mediated immune responses is the activation and clonal expansion of helper T cells. Helper T cell activation is initiated by the interaction of the T cell receptor (TCR)—CD28 complex with an antigen-MHC on the surface of an antigen presenting cell. This interaction mediates a cascade of biochemical events that induce the resting helper T cell to enter a cell cycle (the G0 to G1 transition) and results in the expression of a high affinity receptor for IL-2 and sometimes IL-4. The activated T cell progresses through the cycle proliferating and differentiating into memory cells or effector cells.
In addition to the signals mediated through CD28 [Carreno et al., (2002) Annu Rev Immunol 20: 29-53], the molecule SLAM is also able to provide the second signal for co-stimulation of T cells necessary for proliferation [Aversa et al., (1997) J Immunol 158(9): 4036-4044, Aversa et al., (1997) Immunol Cell Biol 75(2): 202-205]. SLAM is a member of the family of molecules that contain extracelluar Ig-like repeats and also contain a SAP intracellular binding site characterized by the motif TxYxxV/I. Tyrosine phosphorylation of this motif greatly increases the binding of SAP with SLAM. As SAP is associated with X-linked lymphoproliferative disease, a greater understanding of the SAP/SLAM interaction may lead to further insights into treatment of this disease [Howie et al, (2002) Blood 99(3): 957-965, Latour et al., 2001, Nat Immuno 2(8): 681-690, Morra et al. 2001 J Biol Chem 276(39): 36809-36816, Nichols et al., 2001 Nat Immunol 2(8): 665-666].
SLAM has been implicated in Th1 cell response, suggesting that this molecule may play a role in inflammation and autoimmune diseases [Cocks et al., (1995) Nature 376 (6537): 260-263, Aversa et al., (1997) Immunol Cell Bio 75(2): 202-205]. SLAM and CD3 crosslinking on the surface of T cells induces proliferation of T cells and an increase in Interferon gamma (IFN-γ) production. The reasons above lead to the search and discovery of a new member of the SLAM family, PRO20080. It is shown herein, that PRO20080 has homology to SLAM, and like SLAM, has expression in B cells, T cells and memory T cells. PRO20080 is upregulated on activated T cells, exhibits homotypic binding, contains SAP binding motifs and interacts with SAP in T cells. PRO20080 plus CD3 co-stimulation induces the proliferation of T cells and increases the production and secretion of IFN-γ. Evidence is also shown for PRO20080 in the Th1 mediated delayed-type hypersensitivity response, thus making PRO20080 a potential target for treatement of inflammation and Th1 mediated autoimmune diseases.